This invention relates to the use of anti-TAF monoclonal antibody to inhibit Trypanosoma-induced apoptosis of microvascular endothelial brain cells and other target cells.
Human African Trypanosomiasis (HAT, sleeping sickness) is a vector-borne parasitic disease. The parasite (Trypanosoma) is injected into the blood stream via the bite of blood-feeding tsetse flies (Glossina species) and maintains an extra-cellular existence. The parasites invade the central nervous system via the cerebrospinal fluid and cause apoptosis in brain cells leading to mental deterioration, coma and death. Other deleterious manifestations include meningo-encephalitis, neuronal demyelination and apoptosis, blood-brain barrier dysfunction, perivascular infiltration, astrocytosis and, among children who have been treated and cured of the infection, psychomotor and neurological retardation. Countries of tropical Africa, including Benin, Burundi, Burkina Faso, Cameroon, Democratic Republic of Congo, Cote d'Ivoire, Ethiopia, The Gambia, Ghana, Kenya, Liberia, Malawi, Mali, Mozambique, Nigeria, Niger, Rwanda, Senegal, Sudan, Togo, Uganda, Tanzania and Zimbabwe, are all countries with populations suffering from this disease. The use of therapies that would counter the pathologies resulting from this disease would greatly benefit the populations of this region.
It has previously been reported that HAT and other parasitic diseases such as cerebral malaria (the causative agent: Plasmodium falciparum) toxoplasmosis (caused by Toxoplasma gondii), Leishmaniasis (causative agent: Leishmania species) and Chagas disease (T. cruzi as causative agent) result in various apoptosis-mediated pathologies in host organs, including the brain. Human and mouse postmortem immunohistological analysis indicates that HAT causes structural damage to neurons, destroys cells lining the ventricles of the brain and damages brain macrovascular endothelial cells. Interestingly, T cruzi, Toxoplasma, Plasmodium and Leishmania inhibit apoptosis in host macrophages to enhance their proliferation. Although the molecular basis for the pathologies is not clearly understood, previous studies in this laboratory have shown that trypanosome infection resulted in extensive apoptosis at peak parasitaemia in the cerebellum of infected mice.
An initial search of the Entrez protein database revealed that TAF may be a procyclin-like precursor in Trypanosomo brucei stages. Furthermore, database searches on the National Center for Bioinformatics (NCBI) data base for trypanosome proteins identified trypanosome apoptotic factor (TAF) to be procyclin-like and was most likely one of the procyclins or was a procyclin derivative.